The societal consequences of the substance abuse disorders (SADs), cumulated over many millions of individuals, are well known. Every year, hundreds of thousands of lives are simply ended by substance abuse and related social problems, millions of lives are mined, and many millions of lives are adversely impacted directly and even more are impacted indirectly. The financial impact on society is almost as staggering: billions of productive days lost to SAD and secondary effects. This serves as one motivation for theoretical and laboratory medical research into the causes and cures for substance abuse disorders.
Horrendous as they are, such statistics pale in comparison to the results of substance abuse when the impact is measured on any given individual. Affected individuals usually suffer an almost total disruption of every facet of their previous lives: relationships destroyed, families disrupted or ripped apart, finances shattered, reputations mined, careers ended and the list goes on. For those on the “front lines” of addiction treatment, this serves as a very urgent motivation for practical and clinical medical research into the human conditions that lead to substance abuse or addiction. Medical research in the area is thus driven both from the top downwards and from the grass roots upwards.
Biological Bases of Addiction
In the last few decades, it has become increasingly clear on the theoretical side that addiction is in fact either largely or wholly a physiological disorder. Researchers have learned that in a few cases, a small number of genetic variations may be enough to provide an individual with a “predisposition” or “vulnerability” to addiction. It is also becoming clearer that a larger number of milder genetic variations may conspire together to create the same effect. Commonly abused substances themselves alter the function of the brain's normal pleasure response system, apparently as a result of the brain's adaptation to the substance. In fact, regardless of cause, the mere usage of certain chemicals (for example cocaine, alcohol, nicotine and morphine) is linked with changes in the brain's functioning and the associated craving for those substances. The result seems to be a grouping of very similar biochemical neuronal conditions which adversely impact the brain's pleasure responses. The term “Reward Deficiency Syndrome” (RDS) has been coined to describe these disorders. Estimates of the number of individuals that display RDS range as high as one third of the population. U.S. Pat. No. 6,132,724, issued on Oct. 17, 2000 to Blum and entitled “Allelic Polygene Diagnosis of Reward Deficiency Syndrome and Treatment” provides a great deal of background material on RDS and the probable genetic causes thereof.
The brain's neurotransmitter chemicals, receptor cells for those chemicals, and related systems regulating production and maintenance of the appropriate level of these neurotransmitters are at the center of this reward deficiency syndrome. For example, serotonin and dopamine have been implicated in this process: alterations in the metabolic cycle of these substances is part and parcel of substance abuse behavior and recovery therefrom. Dopamine levels may be reduced by substance abuse, and dopamine reception by the neurons may be reduced by substance abuse, thus forming one component of the craving for the substance. It is also possible that the individuals addicted to the substances in question had poor dopamine reception prior to the abuse behavior, and that the poor reception was part of the reason that the individual succumbed to the disease. Following this theory, it is believed that drug abuse breaks down or occupies dopamine connections of the brain, leading to addiction problems. More specifically it is known that dopamine release can be induced by application of precursor amino-acids, thus assisting in reduction of craving. In addition, it is also known that
In addition to dopamine and serotonin, GABA and the opioid peptides are also believed to play a complex role in the reward process. For example, GABA may regulate dopamine release. Studies in rats and mice having a susceptibility to the abuse alcohol show low levels of serotonin and dopamine and increased levels of GABA and opioid peptides. One example of a patent for a medication which acts on the dopamine levels in the brain is U.S. Pat. No. 6,057,368, issued to Dewey et al on May 2, 2000 for “Treatment of Addiction and Addiction-Related Behavior.” The medication taught by the '368 patent uses gamma vinyl GABA as an agent, and is not untypical of modern developments in treatment.
Treatment Regimes
In the past, addiction was treated as a moral or personal flaw, not a physiological condition. Thus treatment often was nonexistent. As the need for therapy became clear, early treatment regimes were instituted. Treatment often consisted of psychological support for the patient, or occasionally, not even that: in some nations, treatment consisted of forcing the individual to undergo “cold turkey” withdrawal in a prison cell. While psychological support for the patient is a necessary part of any treatment regime, methods based only on such support or m a worst case scenario on simultaneous deprivation of both substance and support were only partially successful.
There have been actual attempts to treat the underlying physical symptoms of the problem. Two methods involved in these early attempts to treat the physiology of RDS were the application of agonists and the application of antagonists.
Agonists are substances which themselves are received or otherwise stimulate reception of a neurotransmitter in the neurons, resulting in a “substitution” of one substance, the abused substance, with another: its agonist. The theory is that the craving will be satiated without recourse to the abused substance. Methadone is an example of a heroin agonist. While some positive results were achieved, it is uncertain if methadone treatment actually offered a higher rate of success than psychological support. Numerous “nicotine patches” are offered as a type of substitution therapy for nicotine addiction: while the agonist was in fact the abused substance nicotine, many other dangerous chemicals found in cigarettes, cigars and chewing tobacco are eliminated. In addition, the patient can control the dosage self administered, offering the opportunity to gradually end the nicotine dependency. However, most agonist therapies to date have suffered from a common weakness: they attempt to satisfy craving by replacing the desired substance with some other desirable substance, rather than by offering the patient's body the ability to return the patient's neurochemistry to a healthy state. Obviously, reduction of the craving would be preferable to merely satisfying it. In addition, certain agonist can themselves become addicting, and the patient's tolerance can increase, resulting in the need for higher dosages of the medication, not lower.
Antagonists, on the other hand, actually reduce the potency of the abused substance, resulting in reduced reward for its administration. Naltrexone is an example of a substance which blocks the effects of heroin. In this case, the operative theory is that with reduced reward, the individual will eventually cease to abuse the substance. However, the craving itself is not reduced, merely left unsatisfied by administration of the abused substance. Unfortunately, the action of blocking the effects of the abused substance is rather similar to simply denying the patient the substance in the first place: the craving remains, unsatiated. Worse, the patient's level of well-being spends long periods of time in the “anhedonia” or “dysphoric” (unhappy) phase of the abuse cycle, possibly inflicting as much pain as a “cold turkey” incarceration would have, and demonstrating no overwhelming reduction in the rate of recidivism. Even worse, the internal blockade of the abused substance may simply lead the sufferer to attempt greater dosages of it, with potentially catastrophic results. U.S. Pat. No. 5,824,684 issued to Viner on Oct. 20, 1998, may be taken as an example of a medication including an antagonist agent.
There have also been attempts to combine the agonist and antagonist therapies: See U.S. Pat. No. 5,935,975, issued to Rose et al on Aug. 10, 1999, for “Agonist-Antagonist Combination to Reduce the Use of Nicotine and Other Drugs”. In the method, the agonist (or even the substance abused) is administered to the patient. At the same time or shortly thereafter, the subject is administered the antagonist to the abused substance. In theory, the approach leaves a lesser number of receptors available to respond to the abused substance, while at the same time minimizing the negative effects of a pure antagonist therapy. (See col. 4. lines 38-42.)
Each of these two methods and even combined methods such as the '975 patent do not attempt to return the neurotransmission system to a normal state. While therapy using an agonist temporarily reduces craving, the reduction is simply due to the administration of the abused substance or another having the same psycho-physiological effects. In no case is the actual source of the craving itself—the brain's neurotransmitter imbalances—really lessened, nor is the brain's reward system moved towards a normal balance.
Thus, new and promising therapies have concentrated on a different approach: craving reduction.
Craving-Reduction Therapies
One example of an attempt to treat substance abuse behavior is U.S. Pat. No. 5,013,752, issued May 7, 1991, entitled “Prevention and Treatment of Alcoholism by the use of Dietary Chromium.” While the claim that chromium deficiency is by itself a cause of alcoholism is debatable, the use of chromium has become well established since that time as an ingredient in anti-craving compounds.
Amino-acids have been known for some time as potential agents for dealing with various conditions. U.S. Pat. No. 4,357,343 issued to Madsen, et al on Nov. 2, 1982, entitled “Nutritional Composition for Management of Renal Failure” is a typical example. A recent development in addiction therapy is the use of craving-reduction medications based upon amino-acid precursors of neurotransmitters such as serotonin and dopamine. In this approach, the patient is administered with an oral medication containing substances selected for their ability to promote healthy neurotransmitter function. Certain amino-acids are known to be precursors of the neurotransmitters. For example, the amino-acid 5-hydroxytryptophan is believed to be a precursor of serotonin while the neurotransmitter L-phenylalanine is believed to be a precursor of dopamine. Other amino-acids also function as metabolic precursors of the desired neurotransmitters.
Unfortunately the complexity of the human brain can substantially reduce the efficacy of merely providing a patient with a precursor amino-acid. The reward/pleasure system is not dependent upon any one single biochemical reaction, nor even upon a small number or class of biochemicals, nor does it occur in any one region of the brain. The interactions between the different chemicals in the human anatomy mean that even a subtly different medicinal formulation may have surprising or unexpected results.
For example, certain medicines taught for addiction therapy comprise a single amino-acid. But the interaction of different chemicals within the human anatomy means that this approach may not be efficient, indeed, may not even be effective. In greater detail: the reward/pleasure response in the brain is a complex process in which stimulus in one part of the brain controls stimulus in others, which may in turn lead to stimulation of yet another part of the brain. Each of the steps of release, reception or uptake of neurotransmitters takes place at simultaneously at different locations, and for different substances, and different steps in the neurotransmission cycle may be under the influence of different neurotransmitters or other biochemicals: the release, reception or uptake of neurotransmitters is frequently under the control of other substances: amino-acids, vitamins and minerals. A short example is provided: a low level of a neurotransmitter in the brain can be partially or wholly offset by application of precursor amino-acids which help to build up the level. However, the level of the precursor amino-acids in the brain may be determined by their ability to cross the blood/brain barrier, which in turn may be governed by the amount of a given mineral in the bloodstream, even a mineral normally considered unrelated to the addiction regime. The rate of breakdown and maintenance of the same neurotransmitter in the brain may also be effected or even controlled at that point by the availability of some vitamin or mineral in the system acting upon the enzyme controlling the neurotransmitter. And a mineral which promotes the crossing of the blood/brain barrier by one amino-acid might act to reduce the crossing of the same barrier by other amino-acids. To provide details in this short example: L-tryptophan is a precursor which promotes neurotransmitter activities, while D-phenylalanine promotes neurotransmitter activity by inhibiting enzymatic cleavage. Administration of niacinamide, a form of the vitamin niacin, reduces the premature breakdown of L-tryptophan in the blood stream because tryptophan is typically used in a 60 to 1 ratio to produce niacinamide. Niacinamide later appears to reduce the rate of serotonin breakdown in the brain by inhibiting the action of tryptophan pyrrolase. The mineral calcium assists L-tryptophan to enter the brain, and then further assists conversion of tryptophan to serotonin, but drives other amino-acids into muscle tissue instead. L-tryptophan is desired for its ability to elevate serotonin levels, act as asleep agent, and reduce depression. When a patient is sleeping well and not depressed, the L-tryptophan may actually be removed from alternative embodiments of the present invention. Obviously while L-tryptophan is desirable, it is not desirable to encourage L-tryptophan's action at the expense of the other amino-acids used in the present invention. There are literally hundreds of such interactions taking place, creating a system too complex for present day modeling techniques to interpret.
Thus formulation of amino-acid based anti-craving medications is an unpredictable task, and anti-craving medications tend to involve a spectrum of ingredients designed to assist the combined efficacy or efficiency of the anti-craving effect. Examples of anti-craving compounds show the wide variation in formulations. For example, as referenced previously, U.S. Pat. No. 6,132,724, issued on Oct. 17, 2000 to Blum and entitled “ALLELIC Polygene Diagnosis of Reward Deficiency Syndrome and Treatment” provides a great deal of background material on RDS and the probable genetic causes thereof, and furthermore discloses and claims an oral anti-craving composition comprising a substance which inhibits the enzymatic destruction of a neuropeptidyl opiate, a neurotransmitter-precursor amino-acid, chromium, and either an herbal extract from Rhodiola rosea or huperzine. U.S. Pat. No. 4,761,429 (“Enkephalinase and Endorphinase Inhibitors as Anti-Craving Compositions”, issued Aug. 2, 1988) and U.S. Pat. No. 5,189,064 (“Treatment of Cocaine Disorders”, issued Feb. 23, 1993) both to the same individual as the '724 patent, disclose craving reduction by means of administering one or more amino-acids which “inhibit the destruction of neuropeptidyl opiates . . . in an amount sufficient to reduce the craving”. The same individual (Dr. Kenneth Blum, usually considered a leader in the field) has also stated that he has a pending patent application which was filed on Mar. 21, 2000, (application and number are unavailable to the present applicant) regarding short-term bolus administration of amino-acids and Rhodiola extract.
Another excellent background article may be found in SUBSTANCE AND ALCOHOL ACTIONS/MISUSE, Vol. 3, pp. 231-239, dated 1982, in the name of author Seymour Ehrenpreis, Ph.D., regarding the use of D-phenylalanine and other enkephalinase inhibitors in therapeutic applications. At page 235, this article discusses linkage between development of tolerance to the analgesic actions of opiates and physical dependence with endorphins and states that this “immediately suggests important clinical uses for enkaphalinase inhibitors . . . . This in itself might well inhibit the development of dependence. DPA (D-phenylalanine) or other enkephalinase inhibitors could also be employed to ameliorate symptoms of withdrawal in heroin or morphine addicts.”
One barrier to efficient usage of administered amino-acids, albeit a barrier present in all human beings rather than just those suffering from substance abuse disorder, is the blood/brain barrier. U.S. Pat. No. 4,650,789 and U.S. Pat. No. 4,897,380, respectively issued to Pollack and to Pollack, et al, on Mar. 17, 1987 and Jan. 20, 1990, for “Method and Composition for Increasing Production of Serotonin” and “Method and Composition for Relieving Dietary-Related Disorders” also propose amino-acid medications for neurotransmitter re-balancing. These two patents both teach the use of L-tryptophan as the amino-acid, along with ingredients designed to assist it across the blood/brain barrier. However, in order to assist L-tryptophan in crossing the blood/brain barrier, both patents suggest the use of fructose to drive other amino-acids in the patient's blood stream into the muscles, thus increasing the relative concentration of L-tryptophan and speeding its passage to the brain. Obviously, this is counterproductive if the objective is to administer a group of amino-acids.
Another example of this problem is the administration of cyanocobalamin (vitamin B12). While cyanocobalamin is the form of vitamin B12 which is metabolized in oral administration, and thus the form known in the art in anti-craving compositions, it is also a form which must first pass through the metabolic machinery of the liver to become hydroxy-cobalamin, then be metabolized by the liver a second time in order to become the metabolically active form of the agent vitamin B12. This known process is disadvantageous for use by substance abuse patients, as will be explained below in the detailed description of the present invention.
All of these compositions contain weaknesses in terms of their practical efficiency of use by the body of a substance abuser. In some cases, important components are administered in a form which decreases their ability to be absorbed into the blood stream at all. Some of the same references offer important active agents in forms which are slow or difficult to metabolize in the body of an individual who has abused substances. Other references teach the use of agents such as fructose which assist the use of one amino-acid at the expense of all others. Finally, compounding of numerous amino-acids, vitamins and minerals into a formula suitable for IV administration, with the consequent advantages thereof, is quite difficult. Amino-acid medications via intravenous drip may require the administration of a dozen or more vials of medication. Combinations of numerous ingredients, however, are likely to precipitate or react in storage. This both teaches away from the creation of multiple agent medications and also makes it difficult to find suitable formulas for such agents.
A second issue which arises is that of form of administration. The efficacy of a given medication will be a function of the concentration in the body of the individual achieved by a given method of administration and the time for which that concentration is maintained. Known oral medications are inefficient in terms of the concentration achieved. Direct injection via short-term bolus therapy on the other hand will merely “spike” the desired active agents in the body of the patient without providing a substantial amount of time for the agents to take effect. The knowledge that the active anti-craving agents would quickly depart the metabolic system appears to have caused previous researchers in the field to tend to avoid water soluble forms of the active anti-craving agents.
Oral administration suffers from barriers between administration and brain cell receptor sites, and generally allows lower dosages.
Thus, a need remains for an anti-craving medication which is formulated and administered for high efficacy due to the combination of active agents, but which is also formulated for efficient usage by the body of an individual suffering from the typical conditions of a substance abuser.
The present applicants have previously shown that long time IV drip is one effective way to elevate levels of desirable nutrients in the blood of patients. Building on that, the present application teaches that oral medications, if properly formulated may be used in either a maintenance role (following a corrective course of IV therapy) or in an initial corrective role.